The project entails identification ofmetabolic defects associated with the pathophysiology of Down syndrome (DS). Subsequently, the implicated metabolic processes will be probed in Alzheimer's disease (AD) and in healthy aging. Development of bioanalytical techniques to study brain chemistry is an integral part of this study. Profiles of polyols in DS were examined in view of the functional abnormalities that constitute its phenotype. Abnormal levels of polyols lead to neurological disorders and cataract formation in humans (diploids). Several polyol species in cerebrospinal fluid (CSF) and plasma from DS and age-matched control subjects were quantitated by a mass spectrometric technique based on generation of a unique fragment ion. The CSF concentration and the CSF to plasma concentration ratio of myo-inositol were significantly elevated in DS. Other polyols in CSF and plasma myo-inositol were unaltered. A positive correlation between the level of CSF myo-inositol and age was observed in controls and not in DS. myo-Inositol plays a central role in signal transduction and osmoregulatory processes in the brain. Analysis of polyols in AD showed no significant increase in CSF myo-inositol. However, a correlation between the levels of myo-inositol in CSF and plasma was lost in AD as in DS. Physostigmine is a candidate cholinergic drug for treating AD subjects. The plasma concentration profile of this drug is routinely being obtained by a HPLC technique developed in this laboratory. Additionally, structure analysis of rat brain phosphatidylcholine (PC) and phosphatidylinositol was carried out. Two polyunsaturated molecular species of PC into which radiolabeled arachidonate incorporated with high specific activity were identified. These molecular species may play an important role in signal transduction in the brain.